1. Technical Field
This invention provides a method of preparing drugs comprising tricyclic ring structures that possess 3 nitrogen atoms. More specifically, the invention provides a method of preparing 4-amino-1H-imidazo(4,5-c)quinolines and acid addition salts thereof.
2. Background Art
4-amino-1-isobutyl-1H-imidazo(4,5-c)quinoline (imiquimod; compound of formula (1), wherein R1=isobutyl, R2═H) is an immune-response modifier that induces various cytokines, including interferon-α. It is marketed as a 5% cream under the tradename ALDARA® (3M Pharmaceuticals, St. Paul, Minn.), and has been widely used to treat genital warts in humans.

Two procedures for preparing a compound of formula (1) from the corresponding 4-chloro analog of formula (2) have been reported. The first procedure is a one-step ammonolysis procedure (Scheme 1).

U.S. Pat. No. 4,689,338 ('338 patent) and Shen et al., Chem. Res. & Appln., 2001, 13, 249-252 (the Shen article), specifically disclose Scheme 1 procedures. The '338 patent discloses the reaction of the compound of formula (2) (R3=methyl, isobutyl, 2,3-dihydroxypropyl, phenyl, 4-methoxyphenyl, or 4-fluorophenyl; R4=hydrogen or methyl) with ammonia or ammonium hydroxide in a sealed vessel for 16-18 hours at 150° C.-155° C. The '338 patent does not disclose the obtained yield. The Shen article discloses the reaction of the compound of formula (2) (R3=isobutyl; R4=hydrogen) with aqueous ammonia in methoxy ethanol solvent in a sealed vessel for 4 hours at 100° C. The obtained yield of the compound of formula (1) (R1=isobutyl, R2═H) is reported to be 61%.
One disadvantage of the ammonolysis procedure (Scheme 1) is that the ammonolysis reaction must be conducted at elevated temperature in a sealed reaction vessel. This poses an undesirable safety risk.
The second procedure is a two-step procedure (Scheme 2). In the first step of the second procedure, a 4-chloro compound of formula (2) is subjected to an addition/elimination reaction with benzylamine to provide a benzylamino intermediate. In the second step of the second procedure, the benzylamino intermediate is hydrogenolyzed to provide a compound of formula (1).

U.S. Pat. No. 6,069,149 ('149 patent) and the Shen article specifically disclose Scheme 2 procedures. The '149 patent discloses that the first step is performed by heating a compound of formula (2) (R3=3-(tert-butoxycarbonylamino)propyl, 4-(tert-butoxycarbonylamino)butyl; R4=hydrogen) in neat benzylamine for three hours. The benzylamino intermediate is isolated by distilling away excess benzylamine, and purified using silica gel column chromatography. The Shen article discloses that the first step is performed by heating a compound of formula (2) with benzylamine and potassium carbonate in methoxy ethanol solvent for eight hours. The benzylamino intermediate is isolated by distilling away the solvent.
The '149 patent discloses that the second step is performed by refluxing the benzylamino intermediate with Pd(OH)2/C (Pearlman's catalyst) in a weak acid (i.e., formic acid) for 1-2 days. However, the yield of the compound of formula (1) (R1=3-aminopropyl, 4-aminobutyl; R2═H) is reported only to be 37-42%. The Shen article discloses an attempt to perform the second step by heating the benzylamino intermediate with hydrogen and Pd/C at 80° C. under acidic conditions. The Shen article states that the attempt failed.
One disadvantage of the first step in the second procedure (Scheme 2) is that the reaction solvent must be removed by distillation to isolate the benzylamino intermediate. In addition, purification using silica gel chromatography is required when the addition/elimination reaction is performed neat in benzylamine. Such distillation and chromatography procedures are costly and undesirable on an industrial scale. One disadvantage of the second step in the second procedure (Scheme 2) is that the hydrogenolysis reaction is proven to be difficult, and proceeds at a low yield even after a long reaction time. Presently, there are no suitable alternatives for the hydrogenolysis reaction.
There is a continuing need for an improved method of preparing 4-amino-1H-imidazo(4,5-c)quinolines.